Benzisothiazole and benzisoxazole piperazine derivatives

ABSTRACT

Disubstituted N,N-piperazinyl derivatives are disclosed wherein one substituent is benzisothiazol-3-yl or benzisoxazol-3-yl and the other is alkylene attached to heterocycles such as azaspiro[4.5]decanedione, dialkylglutarimide, thiazolidinedione and spirocyclopentylthiazolidinedione or butyrophenone-like groups. The compounds have psychotropic properties and 8-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspior[4.5]decane-7,9-dione is a typical embodiment having selective antipsychotic activity.

BACKGROUND OF THE INVENTION

This invention generally pertains to heterocyclic carbon compoundshaving drug and bio-affecting properties and to their preparation anduse. In particular, the invention is concerned with 1,4-disubstitutedpiperazine derivatives wherein one substituent is1,2-benzoisothiazol-3-yl or 1,2-benzisoxazol-2-yl and the other is aheterocycle (attached via an alkylene chain) or a butyrophenone-like(and corresponding carbinol) radical as depicted: ##STR1##

Wu, U.S. Pat. No. 3,398,151, Wu, et al., U.S. Pat. No. 3,717,634 and,respectively, corresponding Wu, et al., publications--J. Med. Chem., 12,876-881 (1969), 15, 447-479 (1972)--variously describeazaspiro[4.5]decanedione and dialkylglutarimide psychotropic compoundsresembling formula (1) ##STR2## wherein R¹ and R² are alkyl or joined toform --(CH₂)₄ -- or --(CH₂)₅ -- and B inter alia represents phenyl plusvarious heterocyclies (all with optional substituents): ##STR3##

Casten, et al., U.S. Pat. No. 4,182,763 concerns the anxiolytic use ofcompound (4) which is referred to in the biological literature asbuspirone. ##STR4##

Benica, et al., J. Am. Pharmaceutical Association, 451-456 (1950)describes 3,3-dialkylglutarimides wherein R¹ is C₁₋₄ alkyl and R² ishydrogen or C₁₋₄ alkyl as shown in formula (3) and states the compoundslacked significant physiological activity. ##STR5##

Thiazolidinediones are known to the art. For example, Jones, et al., J.Chem. Soc., London, 91-92 (1946) refer to5,5-dialkyl-2,4-thiazolidinedione barbituric acid analogs and disclosethat a 5-spirocyclohexyl-2,4-thiazolidinedione (4) produced narcosis andanalgesia in mice. ##STR6##

Various types of 1,4-substituted piperazine derivatives are also knownto the art as illustrated in the following references.

Great Britain No. 2,023,594A discloses1-(R-alkyl)-4-(3-trifluoromethylthiophenyl)piperazines useful fortreating anxiety and depression having general formula (5) ##STR7##wherein n is 1-3 and R inter alia represents heterocycles such as##STR8## wherein m is 0 or 1 and X is a --S--, --O--, imino, alkyl-iminoor methylene.

Rojsner, et al., Collect. Czech. Chem. Commun., 40(4) 1218-1230 (1975)inter alia describe butyrophenone derivatives of formula (6) as part ofa psychotropic structure-activity-relationship study. ##STR9##

None of the aforementioned references disclose or suggest the1,2-benzisothiazole or 1,2-benzisoxazole piperazine derivatives of theinstant invention.

SUMMARY AND DETAILED DESCRIPTION OF THE INVENTION

In its broadest aspect, the present invention is concerned withpiperazinyl derivatives having neuroleptic (antipsychotic) propertiescharacterized by a compound of Formula (I) ##STR10## wherein Rrepresents the radical ##STR11## in which n is 3 or 4, R₁ and R₂ areindependently lower alkyl of 1 to 4 carbon atoms, Y is oxygen or sulfur,Z is hydrogen or halogen, or a pharmaceutically acceptable non-toxicacid addition salt thereof.

It is to be understood that, as used herein, halogen denotes fluorine,iodine and preferably chlorine and bromine with the term "lower alkyl"referring to both straight and branched chain carbon radicals of from 1to 4 carbon atoms inclusive. Illustrative of these radicals are carbonchains which can be methyl, ethyl, propyl, isopropyl, 1-butyl,1-methylpropyl and 2-methylpropyl.

The pharmaceutically acceptable acid addition salts of the invention arethose in which the anion does not contribute significantly to thetoxicity or pharmacological activity of the salt and, as such, they arethe pharmacological equivalents of the bases of Formula I. They aregenerally preferred for medical usage. In some instances, they havephysical properties which makes them more desirable for pharmaceuticalformulation such as solubility, lack of hygroscopicity, compressibilitywith respect to tablet formation and compatibility with otheringredients with which the substance may be used for pharmaceuticalpurposes. The salts are routinely made by admixture of a Formula I basewith the selected acid preferably by contact in solution employing anexcess of commonly used inert solvents such as water, ether, benzene,ethanol, ethyl acetate and preferably acetonitrile. They may also bemade by metathesis or treatment with an ion exchange resin underconditions in which the anion of one salt of the substance of theFormula I is replaced by another anion under conditions which allow forseparation of the desired species such as by precipitation from solutionor extraction into a solvent, or elution from or retention on an ionexchange resin. Pharmaceutically acceptable acids for the purposes ofsalt formation of the substances of Formula I include sulfuric,phosphoric, hydrochloric, hydrobromic, hydroiodic, citric, acetic,benzoic, cinnamic, mandelic, phosphoric, nitric, mucic, isethionic,palmitic, heptanoic, and others.

The compounds of Formula I wherein R is radical "a, b, c and d" of theinstant invention are obtained by procedures involving alkylation ofpiperazinyl or "imide" intermediates analogous to methods described byWu, et al., patents supra., incorporated herein in entirety byreference. Such methods are illustrated below for preparation of apreferred Formula I compound (R=a, n=4, Y=S, Z=H),8-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione(Ia₁): ##STR12##

In the foregoing reaction schemes, "M" denotes an alkali metal salt andthe specific halogen recited is given only by way of example with othermembers of the halogen class (e.g., chlorine, bromine, iodine) operableas well as suitable displacement groups such as sulfate, phosphate,tosylate, mesylate and the like.

Method A is further generically described as a process for preparing acompound of Formula I wherein R is the radical "a, b, c or d" aspreviously defined therefor which comprises reacting an imidoyl compoundof Formula II

    Imid-A                                                     (II)

wherein "A" is --(CH₂)_(n) --X in which "n" is 3 or 4 and "X" is theacid residue of a reactive ester grouping such as chloride, bromide,iodide, fluoride, sulfate, phosphate, tosylate or mesylate, and "Imid"represents ##STR13## in which R₁ and R₂ are independently lower alkylwith a compound of Formula III ##STR14## wherein "Y" is oxygen or sulfurand "Z" is hydrogen or halogen; in a reaction inert solvent.

Method B is further generically described as a process for preparing acompound of Formula I wherein R is the radical "a, b, c or d" aspreviously defined which comprises reacting an imidoyl compound ofFormula IV

    Imid-M                                                     (IV)

wherein "M" is an alkali metal salt such as sodium, potassium or lithiumand "Imid" represents ##STR15## in which R₁ and R₂ are independentlylower alkyl with a compound of Formula V or V' ##STR16## wherein "X" isthe acid residue of a reactive ester grouping such as chloride, bromide,iodide, fluoride, sulfate, phosphate, tosylate, or mesylate, and inFormula V' is preferably bromine, chlorine or iodine, "n" is 3 or 4, "Y"is oxygen or sulfur, and "Z" is hydrogen or halogen in a reaction inertsolvent.

Method C is further generically described as a process for preparing acompound of Formula I wherein R is the radical "a, b, c and d" aspreviously defined which comprises reacting a compound of Formula VI##STR17## wherein "Imid" represents ##STR18## in which R₁ and R₂ areindependently lower alkyl, "n" is 3 or 4 with a compound of Formula VII##STR19## wherein "halo" is halogen, preferably chlorine or bromine, and"Y" is oxygen or sulfur and "Z" is hydrogen or halogen; in a reactioninert solvent.

Method D is further generically described as a process for preparing acompound of Formula I wherein R is the radical "a, b, c or d" aspreviously defined which comprises reacting an anhydride of FormulaVIII(a, b, c, or d) ##STR20## in which R₁ and R₂ are independently loweralkyl with a compound of Formula IX ##STR21## wherein "n" is 3 or 4, "Y"is oxygen or sulfur and "Z" is hydrogen or halogen; in a reaction inertsolvent.

The foregoing generic embodiments of Methods A, B and C constitute aunitary process for preparing compounds of Formula I wherein R is theradical "a, b, c or d" as previously described which comprisesalkylating a compound of Formula III, IV or VI with an appropriatealkylating intermediate of Formula II, V, V' or VII in a reaction inertsolvent.

Methods A and C are conventionally carried out under reaction conditionsemployed in preparing tertiary amines by alkylating secondary amines.Thus, the compounds of Formula I wherein R is radical "a, b, c and d"are obtained by reacting appropriate intermediates in an inert reactionmedium at temperatures of from about 50° to about 200° C. in thepresence of a base suitable for use as an acid binding agent. Operableinorganic and organic acid binding bases include tertiary amines, alkaliand alkaline earth metal carbonates, bicarbonates, or hydrides withsodium carbonate and potassium carbonate particularly preferred. Asreferred to throughout the specification, the term "inert reactionmedium" refers to any protic or aprotic solvent or diluent which doesnot enter into the reaction to any substantial degree. In this regard,acetonitrile is a particularly preferred solvent with the reactionconveniently carried out at reflux temperature. Satisfactory yields ofthe present compounds are obtained with reaction periods ranging fromabout 2-24 hours. Formula (I) products may be purified bycrystallization techniques from standard solvent media such asacetonitrile, isopropanol, methanol, ethanol and the like and by otherconventional methods such as chromatography employing a silica gelcolumn with mixtures of chloroform and alkanols such as methanol andethanol as eluant.

Method B illustrates a modification of the unitary process of theinstant invention for preparation of Formula I wherein R is radical "a,b, c and d" compounds in which an alkali metal salt of an imideintermediate of Formula IV is alkylated. Standard laboratory proceduresare employed in carrying out this reaction such as those described forthe alkylation step of the Gabriel synthesis--S. Gabriel, Ber. 20, 2224(1887). In the present case, for instance, the reactants are combined inan inert reaction medium at temperatures ranging from 50° C. to 200° C.Toluene and xylene are particularly preferred solvents for carrying outthe reaction but other solvents which do not adversely affect thereaction or reactants can be employed. In this regard, solvents such asdioxane, benzene, dimethylformamide, acetone, acetonitrile, n-butanoland the like are operable. In general, the alkali metal salts (IV) areprepared by treating the corresponding imide precursor with an alkalihydride such as sodium hydride, an alkali alcoholate such as sodiumethoxide, an alkali amide such as sodium amide, an alkali base such assodium hydroxide, potassium hydroxide, an alkali carbonate such assodium carbonate or potassium carbonate in a suitable solvent. It is notnecessary to pre-form the Formula IV alkali metal salts and the imideprecursor and piperazinyl alkylating agent (V or V') can be convenientlycombined in an inert reaction medium in the presence of a base,preferably sodium or potassium carbonate.

Compounds of Formula I wherein R is the radical "e or f" are obtained bya process involving alkylation of a piperazinyl intermediate of FormulaIII ##STR22## wherein "Y" is oxygen or sulfur and "Z" is hydrogen orhalogen with a compound of Formula X ##STR23## wherein "X" is as definedabove and most preferably chlorine or bromine in a reaction inertsolvent to provide the compounds of Formula Ie ##STR24## and thereafterreducing (Ie) to afford the corresponding compounds of Formula If##STR25##

Piperazinyl benzisothiazole and benzisoxazole intermediates of Formula(III) are obtained by reaction of 3-chloro-6-Z-1,2-benzisothiazole or3-chloro-6-Z-1,2-benzisoxazole with excess piperazine at elevatedtemperature. For example, 3-chloro-1,2-benzisothiazole starting materialis prepared by treating 1,2-benzisothiazol-3(2H)one with phosphorouspentachloride at 100°-140° C. for 4 hours. A similar conversion of1,2-benzisoxazol-3-one to 3-chloro-1,2-benzisoxazole is carried out withphosphorus oxychloride/triethylamine according to the procedure of H.Boshagen, Ber. 100, 3326 (1967).

The compounds of the instant invention are useful pharmacological agentswith psychotropic properties. In this regard, they exhibit selectivecentral nervous system activity at non-toxic doses and are of particularinterest as neuroleptic (antipsychotic) agents. As with other knownantipsychotics, the compounds of Formula (I) evoke certain responses instandard in vivo and in vitro pharmacological test systems which areknown to correlate well with relief of anxiety and symptoms of acute andchronic psychosis in man. The following are illustrative of suchconventional in vivo test systems used to classify and differentiate apsychotropic agent from a nonspecific CNS depressant and determinepotential side-effect liabilities (e.g., cataleptic activity). Regardingthe latter, antipsychotic agents as a class are known to producesedation and extrapyramidyl reactions such as acute torsion dystonia,akathiasia, parkinsonism, tardive dyskinesia and autonomic nervoussystem effects.

    ______________________________________                                        Behavioral Test                                                                              Reference                                                      ______________________________________                                        Suppression of conditioned                                                                   Albert, Pharmacologist, 4,                                     avoidance response (CAR)                                                                     152 (1962); Wu et al., J. Med. Chem.,                                         12, 876-881 (1969).                                            Catalepsy      Costall, et al., Psychopharmacologia,                                         34, 233-241 (1974); Berkson, J. Amer.                                         Statist. Assoc., 48, 565-599 (1953).                           Fighting Mouse Tedeschi, et al., J. Pharmacol.                                               Expt. Therap., 125, 28 (1959).                                 Rotarod        Kinnard, et al., J. Pharmacol.                                                Expt. Therap., 121, 354 (1957).                                Apomorphine Stereotypy                                                                       Jannsen, et al., Arzneimittel. Forsch.,                                       17, 841 (1966).                                                ______________________________________                                    

As further indication of the psychotropic activity and specificity ofthe instant compounds, state of the art in vitro central nervous systemreceptor binding methodology can be employed. Certain compounds(commonly referred to as ligands) have been identified whichpreferentially bind to specific high affinity sites in brain tissuedealing with psychotropic activity or potential for side effects.Inhibition of radiolabeled ligand binding to such specific high affinitysites is considered a measure of a compound's ability to affectcorresponding central nervous system function or cause side effects invivo. This principal is employed in the following assays which are givenby way of example.

    ______________________________________                                        Receptor Binding                                                              Assay        Reference                                                        ______________________________________                                        Dopamine     Burt, et al., Molec. Pharmacol., 12, 800                                      (1976); Science, 196, 326 (1977);                                             Creese, et al, Science, 192, 481 (1976).                         Cholinergic  Yamamura, et al., Proc. Natn. Acad. Sci.                                      USA 71 1725 (1974).                                              Alpha-receptor                                                                             Crews, et al., Science 202: 322 (1978);                                       Rosenblatt, et al., Brain Res. 160: 186                                       (1979); U'Prichard, et al., Science 199:                                      197 (1978); U'Prichard, et al., Molec.                                        Pharmacol. 13: 454 (1977).                                       Serotonin Type 2                                                                           Peroutka and Snyder, Molec. Pharmacol.                                        16: 687 (1979).                                                  ______________________________________                                    

According to the pharmacological profile established by theaforementioned tests, the instant compounds of Formula (I) havepromising antipsychotic potential in that they are relatively potent inthe CAR test having oral ED₅₀ values <100 mg/kg body weight and IC₅₀ 'sof <1000 nanomolar in the ³ H spiperone dopamine receptor binding assay.Activity in the CAR test and spiperone assay is considered predictive ofantipsychotic potential in man. Regarding selective antipsychoticactivity, preferred compounds of the invention have significant dopaminereceptor binding activity and suppress rat CAR below cataleptic doses.

A particularly preferred compound in this regard is8-[4-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro-[4.5]decane-7,9-dionewhich exhibits relatively weak cataleptogenic activity in the rat atapproximately 8 times the CAR dose suggesting minimal potential forextrapyramidal side effects.

As previously mentioned, the instant compounds have psychotropicproperties particularly suited to their use as a neuroleptic(antipsychotic) agent. Thus, another aspect of the instant inventionconcerns a process for ameliorating a psychotic state in a mammal inneed of such treatment which comprises systemic administration to saidmammal an effective dose of from about 0.01 to 40 mg/kg body weight of aFormula (I) compound or a pharmaceutically acceptable acid addition saltthereof.

The term systemic administration as used herein refers to oral, rectal,and parenteral (i.e., intramuscular, intravenous, and subcutaneous)routes. Generally, it will be found that when a compound of the presentinvention is administered orally which is the preferred route, a largerquantity of the active agent is required to produce the same effect as asmaller quantity given parenterally. In accordance with good clinicalpractice, it is preferred to administer the instant compounds at aconcentration level that will produce effective neuroleptic(antipsychotic) effects without causing any harmful or untoward sideeffects.

Therapeutically, the instant compounds are generally given aspharmaceutical compositions comprised of an effective antipsychoticamount of a compound of Formula I or a pharmaceutically acceptable acidaddition salt thereof and a pharmaceutically acceptable carrier.Pharmaceutical compositions which provide from about 1 to 500 mg. of theactive ingredient per unit dose are preferred and are conventionallyprepared as tablets, lozenges, capsules, powders, aqueous or oilysuspensions, syrups, elixirs and aqueous solutions.

Preferred oral compositions are in the form of tablets or capsules andmay contain conventional excipients such as binding agents (e.g. syrup,acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone), fillers(e.g. lactose, sugar, maize-starch, calcium phosphate, sorbitol orglycine), lubricants (e.g. magnesium stearate, talc, polyethyleneglycolor silica), disintegrants (e.g. starch) and wetting agents (e.g. sodiumlauryl sulfate). Solutions or suspensions of a Formula I compound withconventional pharmaceutical vehicles are employed for parenteralcompositions such as an aqueous solution for intravenous injection or anoily suspension for intramuscular injection. Such compositions havingthe desired clarity, stability and adaptability for parenteral use areobtained by dissolving from 0.1% to 10% by weight of the active compoundin water or a vehicle consisting of a polyhydric aliphatic alcohol suchas glycerine, propylene glycol, and polyethyleneglycols or mixturesthereof. The polyethyleneglycols consist of a mixture of non-volatile,normally liquid, polyethyleneglycols which are soluble in both water andorganic liquids and which have molecular weights of from about 200 to1500.

The following non-limiting examples serve to illustrate preparation ofspecific compounds of the instant inventions.

EXAMPLE 1 3-(1-Piperazinyl)-1,2-benzisothiazole ##STR26##

A mixture of 3-chloro-1,2-benzisothiazole (37.8 g., 0.235 mole) andpiperazine (304.2 g., 3.53 mole) is heated under an argon atmosphere fora period of 20 hr. at 120° C. in a closed reactor. The reaction mixtureis dissolved in 2 liters of water and the aqueous solution repeatedlyextracted with methylene chloride. Extracts are combined, dried overmagnesium sulfate and concentrated in vacuo. Residual material is takenup in ether, filtered and concentrated in vacuo to afford 24.4 g. (47%)of 3-(1-piperazinyl)-1,2-benzisothiazole free base as a viscous oil.

A sample of the free base converted to the hydrochloride salt in etherwith ethanolic hydrogen chloride and crytallized from methanol-ethanolaffords analytically pure 3-(1-piperazinyl)-1,2-benzisothiazolehydrochloride, m.p. 280° C. (dec.).

Anal. Calcd. for C₁₁ H₁₃ N₃ S.HCl: C, 51.66; H, 5.52; N, 16.43. Found:C, 51.34; H, 5.46; N, 16.16.

EXAMPLE 2 3-(1-Piperazinyl)-1,2-benzisoxazole ##STR27##

A mixture of 3-chloro-1,2-benzisoxazole (19.6 g., 0.128 mole) andpiperazine (110 g., 1.28 mole) is heated for a period of 20 hr. at 120°C. in a closed reactor. The reaction mixture is diluted with water andthe aqueous mixture repeatedly extracted with methylene chloride.Extracts are combined, dried over magnesium sulfate and concentrated invacuo to afford 21.2 g. (82% yield) of3-(1-piperazinyl)-1,2-benzidoxazole free base.

A sample of the free base converted to the hydrochloride salt andcrystallized from methanol-ethanol affords analytically pure3-(1-piperazinyl)-1,2-benzisoxaole hydrochloride, m.p. 326° C. (dec.).

Anal. Calcd. for C₁₁ H₁₃ N₃ O.HCl: C, 55.12; H, 5.89; N, 17.54. Found:C, 55.25; H, 5.82; N, 17.53.

EXAMPLE 38-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione##STR28##

Method A. A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (24.3 g.,0.11 mole) and 8-(4-bromobutyl)-8-azaspiro-[4.5]decane-7,9-dione (33.5g., 0.11 mole), anhydrous potassium carbonate (32.4 g., 0.23 mole) andpotassium iodide (3.9 g., 0.023 mole) in 1 liter of acetonitrile isstirred and heated under reflux for a period of 20 hr. The reactionmixture is filtered, concentrated in vacuo and residual material takenup in 350 ml. of chloroform which is filtered and concentrated in vacuo.The residue is triturated with ether, refrigerated and resulting solidcollected. This material crystallized from acetonitrile (employingactivated charcoal affords a first crop 25.1 g, m.p. 120°-124° C. and asecond crop, 6.0 g, m.p. 123°-126° C. for a total yield of 31.1 g. (64%yield) of the free base form of the title compound. Crystallization fromacetonitrile affords analytically pure 8-[4-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione,m.p. 124°-126° C.

Anal. Calcd. for C₂₄ H₃₂ N₄ O₂ S: C, 65.42; H, 7.32; N, 12.72. Found: C,65.45; H, 7.31; N, 12.75.

NMR (CDCL₃): 1.60 (12H, m); 2.57 (4H, s); 2.62 (6H, m); 3.54 (4H, m);3.79 (2H, m); 7.34 (2H, m); 7.81 (2H, m).

Ethanolic hydrogen chloride (12.3 ml. of 5.7 N) is added to a suspensionof the free base (31 g) in hot isopropanol. The resulting solution iscooled and the precipitate formed collected and dried in vacuo at 80° C.to provide 29.6 g. of8-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dionehydrochloride, m.p. 219°-220° C.

Anal. Calcd. for C₂₄ H₃₂ N₄ O₂ S.HCl: C, 60.43; H, 6.98; N, 11.75.Found: C, 60.57; H, 6.98; N, 11.75.

NMR (DMSO-d₆): 1.55 (12H, m); 2.64 (4H, s); 3.40 (10H, m); 4.05 (2H, d,12.0 Hz); 7.50 (2H, m); 8.10 (2H, m); 12.15 (1H, bs).

A sample of the free base product crystallized from acetonitrilecontaining ethanolic hydrogen chloride affords8-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dionedihydrochloride dihydrate, m.p. 118°-120° C.

Anal. Calcd. for C₂₄ H₃₂ N₄ O₂ S.2HCl.2H₂ O: C, 52.45; H, 6.97; N,10.20. Found: C, 52.68; H, 6.91; N, 10.29.

NMR (DMSO-d₆): 1.55 (12H, m); 2.64 (4H, s); 3.14 (4H, m); 3.58 (6H, m);4.06 (2H, d, 12.0 Hz); 5.48 (4H, s); 7.50 (2H, m); 8.10 (2H, m); 11.60(1H, bs).

Method B. A mixture of 3-(1-piperazinyl)-1,2-benzisothiazole (5.0 g.,0.0228 mole), 1,4-dibromobutane (9.8 g., 0.0456 mole) and finelypowdered anhydrous potassium carbonate (7.9 g., 0.057 mole) in 100 ml.of ethanol is stirred and refluxed for a 16 hr. period. The cooledreaction mixture is filtered and the filtrate concentrated in vacuo.Residual solid heated to reflux with 70 ml. of isopropanol and filtered.Concentration of the filtrate to about one-half volume and refrigerationaffords 5.58 g. (69.1% yield) of8-(1,2-benzoisothiazol-3-yl)-8-aza-5-azoniaspiro[4.5]decane bromide,m.p. 246.5°-253° C.

Anal. Calcd. for C₁₅ H₂₀ BrN₃ S.1/4H₂ O: C, 50.21; H, 5.76; N, 11.71; H₂O, 1.26. Found: C, 50.04; H, 5.68; N, 11.60; H₂ O, 1.50.

A mixture of 3,3-tetramethyleneglutarimide (2.52 g., 0.0151 mole),8-(1,2-benzisothiazol-3-yl)-8-aza-5-azoniaspir[4.5]decane bromide (5.34g., 0.0151 mole), powdered potassium carbonate (2.4 g., 0.0173 mole) in125 ml. of toluene is refluxed and stirred for a 24 hr. period, filteredand evaporated to dryness. Residual material is taken up in boilingtoluene and diluted with hot heptane. The hot solution is treated withactivated charcoal, filtered and cooled to afford 4.46 g. (67.2% yield)of solid, m.p. 109.5°-120° C. Crystallization from methanol affords8-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dionefree base, m.p. 127.5°-130° C.

EXAMPLE 48-[4-[4-(1,2-Benzisoxazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione##STR29##

Reaction of 8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione and3-(1-piperazinyl)-1,2-benzisoxazole according to the procedure ofExample 3 and crystallization of the free base from isopropanol affordsa 40% yield of8-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dionehemihydrate, m.p. 96°-98° C.

Anal. Calcd. for C₂₄ H₃₂ N₄ O₃.1/2H₂ O: C, 66.49; H, 7.68; N, 12.93; H₂O, 2.08. Found: C, 66.59; H, 7.59; N, 12.87; H₂ O, 2.38.

NMR (CDCl₃): 1.55 (12H, m); 2.41 (2H, m); 2.57 (4H, s); 2.60 (4H, m);3.57 (4H, m); 3.89 (2H, m); 7.15 (1H, m); 7.41 (2H, m); 7.66 (1H, d, 8.0Hz).

EXAMPLE 53-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]butyl]-2,4-thiazolidinedion##STR30##

(a) 2,4-Thiazolidinedione sodium salt. 2,4-Thiazolidinedione (11.71 g.,0.1 mole) and 100 ml. of 0.1 N sodium hydroxide (0.1 mole) are mixed andwarmed as necessary to effect solution. Concentration of the basicsolution under reduced pressure affords a semisolid which, with repeatedacetone trituration and removal of solvent in vacuo, provides acrystalline solid. This material is collected, washed with acetone, anddried at 60° C. in vacuo to provide 15.1 g. (95% yield) of the sodiumsalt of 2,4-thiazolidinedione, m.p. 225° C. (dec.).

(b) 3-(4-Bromobutyl)-2,4-thiazolidinedione. The 2,4-thiazolidinedionesodium salt (13.91 g., 0.1 mole) is added to a solution of1,4-dibromobutane (64.77 g., 0.3 mole) in 500 ml. of drydimethylformamide. After stirring the mixture at room temperature for a16 hr. period, the resulting clear solution is concentrated in vacuo andresidual material dissolved in chloroform, filtered, and concentrated invacuo to an amber oil. Distillation of the oil affords 20.62 g. (81%yield) of 3-(4-bromobutyl)-2,4-thiazolidinedione, b.p. 105°-115° C. at0.02 mmHg.

(c)3-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]butyl]-2,4-thiazolidinedioneDihydrochloride. Reaction of 3-(4-bromobutyl)-2,4-thiazolidinedione with3-(1-piperazinyl)-1,2-benzoisothiazole according to the procedure ofExample 3 and conversion of the free base to the hydrochloride salt inacetonitrile affords a 45% yield of3-[4-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinyl]butyl]-2,4-thiazolidinedionedihydrochloride, m.p. 200°-202° C., from acetonitrile.

Anal. Calcd. for C₁₈ H₂₂ N₄ O₂ S₂.2HCl: C, 46.65; H, 5.22; N, 12.09.Found: C, 46.35; H, 5.31; N, 13.10.

NMR (DMSO-d₆): 1.70 (4H, m); 3.16 (4H, m); 3.54 (6H, m); 4.06 (2H, d,12.0 Hz); 4.21 (2H, s); 7.51 (2H, m); 8.10 (2H, m); 11.55 (1H, bs).

EXAMPLE 63-[4-[4-(1,2-Benzisoxazol-3-yl)-1-piperazinyl]butyl]-2,4-thiazolidinedione##STR31##

Reaction of 3-(4-bromobutyl)-2,4-thiazolidinedione with3-(1-piperazinyl)-1,2-benzisoxazole according to the procedure ofExample 3 affords a 44% yield of3-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]butyl]-2,4-thiazolidinedionehydrate, m.p. 104.5°-106.6° C., from methanol.

Anal. Calcd. for C₁₈ H₂₂ N₄ O₃ S.1/4H₂ O: C, 57.06; H, 5.99; N, 14.79;H₂ O, 1.19. Found: C, 57.17; H, 5.98; N, 14.78; H₂ O, 1.28.

NMR (CDCl₃): 1.64 (4H, m); 2.42 (2H, t, 6.6 Hz); 2.61 (4H, m); 3.58 (6H,m); 3.92 (2H, s); 7.42 (4H, m).

EXAMPLE 78-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]butyl]-6-thia-8-azaspiro[4.4]nonane-7,9-dione##STR32##

(a) 5-Spirocyclopentyl-2,4-thiazolidindione Sodium Salt.5-Spirocyclopentyl-2,4-thiazolidindione obtained according to Jones, etal., supra. (1.71 g., 0.01 mole) and 10 ml. of 1.0 N sodium hydroxide(0.01 mole) are mixed and warmed as necessary to effect solution.Concentration of the basic solution with repeated acetone triturationand removal of solvent in vacuo affords 1.66 g. (86% yield) of thesodium salt of 5-spirocyclopentyl-2,4-thiazolidindione, m.p. 243°-245°C.

(b) 3-(4-Bromobutyl)-5-spirocyclopentyl-2,4-thiazolidindione.5-Spirocyclopentyl-2,4-thiazolidindione sodium salt (3.83 g., 0.019mole) in 180 ml. of dimethylformamide is slowly added to1,4-dibromobutane (12.84 g., 0.059 mole) in 20 ml. of dimethylformamide.The mixture is stirred at room temperature for a 16 hr. period and thenconcentrated under reduce pressure. Residual material dissolved inchloroform, filtered and the filtrate concentrated and distilled affords4.96 g. (85% yield) of3-(4-bromobutyl)-5-spirocyclopentyl-2,4-thiazolidinedione, b.p.122°-126° C. at 0.04 mmHg.

(c) Title Product hydrochloride hydrate. Reaction of3-(4-bromobutyl)-5-spirocyclopentyl-2,4-thiazolidinedione with3-(1-piperazinyl)-1,2-benzisothiazole and conversion of the free base tothe hydrochloride salt according to the procedure of Example 3 affordsan 84% yield of8-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-6-thia-8-azaspiro[4.4]nonane-7,9-dionehydrochloride hydrate, m.p. 214° C., from ethanol.

Anal. Calcd. for C₂₂ H₂₈ N₄ O₂ S₂.HCl.0.1 H₂ O: C, 54.72; H, 6.10; N,11.60; H₂ O, 0.37. Found: C, 54.40; H, 6.22; N, 11.40; H₂ O, 0.46.

NMR (DMSO-d₆): 1.74 (8H, m); 2.20 (4H, m); 3.15 (4H, m); 3.52 (6H, m);4.05 (2H, d, 12.0 Hz); 7.49 (2H, m); 8.09 (2H, m); 11.60 (1H, bs).

EXAMPLE 88-[4-[4-(1,2-Benzisoxazol-3-yl)-1-piperazinyl]butyl]-6-thia-8-azaspiro[4.4]nonane-7,9-dione##STR33##

Reaction of 3-(4-bromobutyl)-5-spirocyclopentyl-2,4-thiazolidinedionewith 3-(1-piperazinyl)-1,2-benzosoxazole and conversion of the free baseto the hydrochloride salt according to the procedure of Example 3affords an 88% yield of8-[4-[4-(1,2-benzoisoxazol-3-yl)-1-piperazinyl]butyl]-6-thia-8-azaspiro[4.4]nonane-7,9-dionehydrochloride hydrate m.p. 212°-214° C., from isopropanol.

Anal. Calcd. for C₂₂ H₂₈ N₄ O₃ S.HCl.0.75 H₂ O: C, 55.22; H, 6.42; N,11.71; H₂ O, 2.82. Found: C, 54.92; H, 6.23; N, 11.51; H₂ O, 2.42.

NMR (DMSO-d₆): 1.75 (8H, m); 2.18 (4H, m); 3.34 (10H, m); 4.07 (2H, d,12.0 Hz); 7.44 (3H, m); 7.98 (1H, m); 11.20 (1H, bs).

EXAMPLE 91-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]butyl]-4-methyl-4-propyl-2,6-piperidinedione##STR34##

(a) N-(4-(Bromobutyl)-3-methyl-3-n-propylglutarimide. A mixture of3-methyl-3-n-propylglutarimide (25 g., 0.15 mole) obtained according toN. S. Benica, et al., supra, 1,4-dibromobutane (33.5 g., 0.15 mole), andpotassium carbonate (4.6 g., 0.29 mole) is stirred and refluxed for aperiod of 16 hr. in 250 ml. acetonitrile. Insolubles are removed byfiltration and the filtrate concentrated to an oil in vacuo.Distillation of residual oil affords 42.5 g. (95%) ofN-(4-bromobutyl)-3-methyl-3-n-propylglutarimide as a light yellow oil,b.p. 165°-190° at 0.09 mm.

(b) Title product hydrochloride. Reaction ofN-(4-bromobutyl)-3-methyl-3-n-propylglutarimide with3-(1-piperazinyl)-1,2-benzisothiazole and conversion of the free base tothe hydrochloride salt according to the procedure of Example 3 affords1-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-4-methyl-4-propyl-2,6-piperidinedionehydrochloride, m.p. 163°-165° C.

Anal. Calcd. for C₂₄ H₃₄ N₄ O₂ S.HCl: C, 60.18; H, 7.37; N, 11.70.Found: C, 60.13; H, 7.46; N, 11.52.

NMR (CDCl₃): 0.91 (3H, t, 6.0 Hz); 1.01 (3H, s); 1.29 (2H, m); 1.68 (2H,q, 6.8 Hz); 1.85 (4H, m); 2.53 (4H, s); 3.25 (6H, m); 3.79 (2H, t, 6.9Hz); 4.08 (4H, m); 7.41 (2H, m); 7.84 (2H, m); 12.70 (1H, bs).

EXAMPLE 101-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]butyl-4,4-dimethyl-2,6-piperidinedione##STR35##

A mixture of N-(4-bromobutyl)-3,3-dimethylglutarimide (4 g., 0.0145mole) obtained according to the procedure of Example 9,3-(1-piperazinyl)-1,2-benzisothiazole (3.18 g., 0.0145 mole), anhydrouspotassium carbonate (20.04 g., 0.145 mole) and potassium iodide (0.25g., 0.0015 mole) in 150 ml. of acetonitrile is stirred and refluxed fora period of 12 hr. The reaction mixture is filtered, concentrated invacuo and residual material triturated with ether. Crystallization ofthe solid thus obtained from ether affords a 64% yield of analyticallypure1-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-4,4-dimethyl-2,6-piperidinedione,m.p. 146°-147° C.

Anal. Calcd. for C₂₂ H₃₀ N₄ O₂ S: C, 63.74; H, 7.29; N, 13.52. Found: C,63.78; H, 7.11; N, 13.71.

NMR (CDCl₃): 1.06 (6H, s); 1.56 (4H, m); 2.48 (4H, s); 2.60 (6H, m);3.55 (4H, m); 3.80 (2H, t, 7.0 Hz); 7.38 (2H, m); 7.85 (2H, m).

EXAMPLE 111-[4-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]butyl]-4,4-diethyl-2,6-piperidinedione##STR36##

(a) N-(4-Bromobutyl)-3,3-diethylglutarimide. A solution of3,3-diethylglutarimide (7.0 g., 0.041 mole) obtained according to theprocedure of N. S. Benica, et al., supra., and sodium hydroxide (1.64g., 0.041 mole) in 100 ml. of 70% ethanol is warmed and stirred for a 20min. period. Concentration of the mixture in vacuo provides the solidsodium salt of 3,3-diethylglutarimide which is suspended in 150 ml. ofdimethylformamide and treated with 1,4-dibromobutane (17.7 g., 0.082mole). The resulting mixture is stirred at room temperature for a periodof 48 hr. and then concentrated in vacuo. Residual material dissolved inchloroform, filtered, and the filtrate concentrated and distilledaffords 11.4 g. (93% yield) of N-(4-bromobutyl)-3,3-diethylglutarimide.

(b) Title product hydrochloride hydrate. Reaction ofN-(4-bromobutyl-3,3-diethylglutarimide and3-(1-piperazinyl)-1,2-benzisothiazole and conversion of the free base tothe hydrochloride salt in isopropanol according to the procedure ofExample 3 affords1-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-4,4-diethyl-2,6-piperidinedionehydrochloride hydrate, m.p. 179°-183° C., from acetonitrile.

Anal. Calcd. for C₂₄ H₃₄ N₄ O₂ S.HCl.0.25H₂ O: C, 59.61; H, 7.40; N,11.59. Found: C, 59.50; H, 7.24; N, 11.50.

NMR (DMSO-d₆): 0.79 (6H, t, 7.5 Hz); 1.32 (4H, q, 7.5 Hz); 1.60 (4H, m);2.55 (4H, s); 3.44 (10H, m); 4.07 (2H, m); 7.52 (2H, m); 8.11 (2H, m);11.78 (1H, bs).

EXAMPLE 124-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]-1-(4-fluorophenyl)-1-butanone##STR37##

(a) 2-(3-Chloropropyl)-2-(4-fluorophenyl)-1,3-dioxane. As set forth inChem. Abs. 63, 9959b (1965), a mixture of4-chloro-4'-fluorobutyrophenone (20 g.), ethylene glycol (6.9 g.) andp-toluensulfonic acid (0.05 g.) in 50 ml. of benzene is refluxed for 30hr. collecting the water formed. Concentration of the reaction mixturein vacuo affords 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxane.

(b) Title product hydrochloride. A mixture of2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxane (4.31 g., 0.0176mole), 3-(1-piperazinyl)-1,2-benzisothiazole (3.86 g., 0.0176 mole),powdered potassium carbonate (2.43 g., 0.0176 mole) and potassium iodide(0.88 g., 0.0053 mole) in 180 ml. of dry acetonitrile is refluxed for a20 hr. period. The reaction mixture is filtered, concentrated in vacuoand residual oil dissolved in chloroform and filtered. Concentration ofthe filtrate affords an oily residue which is taken up in 100 ml. ofethanol containing 10 ml. of 3 N hydrochloric acid and refluxed for 15min. period. Acetonitrile is added to the cooled mixture and the solidobtained collected, 3.3 g. m.p. 248°-250° C. Crystallization of thismaterial from ethanol affords analytically pure4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-1-(4-fluorophenyl)-1-butanonehydrochloride, m.p. 251°-254° C.

Anal. Calcd. for C₂₁ H₂₂ FN₃ OS.HCl: C, 60.06; H, 5.52; N, 10.01. Found:C, 59.70; H, 5.47; N, 9.78.

NMR (DMSO-d₆): 2.12 (2H, m); 3.25 (6H, m); 3.56 (4H, m); 4.06 (2H, d,12.0 Hz); 7.41 (4H, m); 8.08 (4H, m); 11.60 (1H, bs).

EXAMPLE 13α-[3-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]propyl]-4-fluorobenzenemethanol##STR38##

Sodium borohydride (1.0 g., 0.026 mole) is added portionwise to astirred suspension of4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]-1-(4-fluorophenyl)-1-butanonehydrochloride (3.34 g., 0.008 mole) in 150 ml. of absolute ethanol. Themixture is stirred for a 20 hr. period, acidified with ethanolichydrogen chloride, stirred for an additional 2 hr. period andconcentrated in vacuo. Residual material is partitioned betweenchloroform and 1 N aqueous sodium hydroxide and the chloroform phasedried over magnesium sulfate and concentrated in vacuo to afford 2.31 g.(69% yield) of the title compound as the free base. The free base isconverted to the hydrochloride in ethanol with ethanolic hydrogenchloride to affordα-[3-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]propyl]-4-fluorobenzenemethanolhydrochloride, m.p. 200°-202° C.

Anal. Calcd. for C₂₁ H₂₄ FN₃ OS.HCl: C, 59.78; H, 5.97; N, 9.96. Found:C, 59.34; H, 5.95; N, 9.82.

NMR (DMSO-d₆): 1.70 (4H, m); 3.40 (8H, m); 4.05 (2H, d, 12.0 Hz); 4.59(1H, m); 5.30 (1H, bs); 7.35 (6H, m); 8.10 (2H, m); 11.20 (1H, bs).

EXAMPLE 144-[4-(1,2-Benzisoxazol-3-yl)-1-piperazinyl]-1-(4-fluorophenyl)-1-butanone##STR39##

Reaction of 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxane with3-(1-piperazinyl)-1,2-benzisoxazole according to the procedure ofExample 12 and conversion of the free base to the hydrochloride saltaffords a 25% yield of4-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]-1-(4-fluorophenyl)-1-butanonehydrochloride, m.p. 260°-262°, from methanol (25% yield).

Anal. Calcd. for C₂₁ H₂₂ FN₃ O₂.HCl: C, 62.46; H, 5.75; N, 10.41. Found:C, 62.18; H, 5.59; N, 10.50.

NMR (DMSO-d₆): 2.11 (2H, m); 2.56 (2H, m); 3.40 (8H, m); 4.12 (2H m);7.33 (5H, m); 7.60 (1H, m); 8.06 (2H, m); 11.20 (1H, bs).

EXAMPLE 15α-[3-[4-(1,2-Benzisoxazol-3-yl)-1-piperazinyl]propyl]-4-fluorobenzenemethanol##STR40##

Reduction of4-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]-1-(4-fluorophenyl)-1-butanonehydrochloride (2.0 g., 0.005 mole) with sodium borohydride (0.57 g.,0.015 mole) in 200 ml. of absolute ethanol is carried out according tothe procedure of Example 13. Residual material remaining afterconcentration of the acidified mixture is basified with sodium hydroxideand extracted with chloroform. The combined extracts are dried overmagnesium sulfate, concentrated in vacuo and triturated with ether togive 1.2 g. of the free base product. Crystallization of this materialfrom ethanol affords analytically pureα-[3-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]propyl]-4-fluorobenzenemethanol,m.p. 142.5°-143.5° C.

Anal. Calcd. for C₂₁ H₂₄ FN₃ O₂ : C, 68.28; H, 6.55; N, 11.38. Found: C,68.13; H, 6.56; N, 11.43.

NMR (CDCl₃): 1.79 (4H, m); 2.60 (6H, m); 3.64 (4H, m); 4.68 (1H, m);7.22 (8H, m).

EXAMPLE 168-[4-[4-(2,1-Benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione##STR41##

(a) 3-(1-Piperazinyl)-2,1-benzisothiazole. A mixture of3-chloro-2,1-benzisothiazole (4.79 g., 0.028 mole obtained according toAlbert, et al., J. Het. Chem., 15, 529 (1978) and piperazine (36.2 g.,0.42 mole) is heated for a period of 18 hr. at 120° C. in a closedreactor. The cooled reaction mixture is dissolved in 400 ml. of waterand the aqueous solution extracted with ether and then with methylenechloride. The combined extracts are dried over magnesium sulfate andconcentrated in vacuo to afford 5.67 (90%) of3-(1-piperazinyl)-2,1-benzisothiazole free base.

A sample of the free base converted to the hydrochloride salt in ethanolwith ethanolic hydrogen chloride affords analytically pure3-(1-piperazinyl)-2,1-benzisothiazole dihydrochloride, m.p. 274°-276° C.(dec.).

(b) Title product dihydrochloride dihydrate. A mixture of3-(1-piperazinyl)-2,1-benzisothiazole (4.0 g., 0.018 mole) and8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione (5.5 g., 0.018 mole),anhydrous potassium carbonate (4.98 g., 0.036 mole) and potassium iodide(0.83 g., 0.005 mole) in 100 ml. of acetonitrile is stirred at refluxtemperature for a period of 20 hr. The reaction mixture is filtered,concentrated in vacuo and residual material triturated with ether toafford 7.38 g., (93% yield) of the title product free base. Conversionof the free base to the hydrochloride salt in ethanol with ethanolichydrogen chloride and crystallization from ethanol affords 5.34 g. (57%yield) of analytically pure8-[4-[4-(2,1-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro-[4.5]decane-7,9-dionedihydrochloride hemihydrate, m.p. 225°-227° C. (dec.).

Anal. Calcd. for C₂₄ H₃₂ N₄ O₂ S.2HCl.0.5H₂ O: C, 55.17; H, 6.76; N,10.73. Found: C, 55.55; H, 6.84; N, 10.97.

NMR (DMSO-d₆): 1.52 (12H, m); 2.63 (4H, s); 3.57 (12H, m); 7.05 (1H, m);7.46 (2H, m); 7.90 (1H, d, 8.0 Hz); 9.35 (2H, bs).

EXAMPLE 178-[4-[4-(6-Chloro-1,2-benzisoxazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione##STR42##

(a) 3-(1-Piperazinyl)-6-chloro-1,2-benzisoxazole. A mixture of3,6-dichloro-1,2-benzisoxazole and piperazine is reacted according tothe procedure of Example 2. The3-(1-piperazinyl)-6-chloro-1,2-benzisoxazole intermediate is isolated in79% yield and used without further purification.

(b) Title product. Reaction of8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione (2.03 g., 0.067 mole)and 3-(1-piperazinyl)-6-1,2-benzisoxazole (1.6 g., 0.067 mole) accordingto the procedure of Example 3 provides the crude base which is convertedto the hydrochloride salt and crystallized from ethanol. The salt istaken up in water and basified with ammonium hydroxide to provide thefree base which crystallized from isopropanol affords 0.3 g. (10% yield)of analytically pure8-[4-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione,m.p. 127.5°-128.5° C.

Anal. Calcd. for C₂₄ H₃₁ ClN₄ O₃ : C, 62.81; H, 6.81; N, 12.21. Found:C, 62.73; H, 6.83; N, 12.35.

NMR (DMSO-d₆): 1.48 (12H, m); 2.32 (2H, m); 2.60 (4H, s); 3.40 (10H, m);7.30 (1H, dd, 8.0, 1.8 Hz); 7.74 (1h, d, 1.8 Hz); 7.98 (1H, d, 8.0 Hz).

What is claimed is:
 1. A compound of Formula (I) ##STR43## wherein Rrepresents the radical ##STR44## wherein n is 3 or 4,R₁ and R₂ areindependently lower alkyl of 1 to 4 carbon atoms, Y is oxygen or sulfur,Z is hydrogen or halogenor a pharmaceutically acceptable non-toxic acidaddition salt thereof.
 2. The compound of claim 1 wherein R is the8-azaspiro[4.5]decane-7,9-dione radical (a) or a pharmaceuticallyacceptable acid addition salt thereof.
 3. The compound of claim 2 whichis8-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dioneor a pharmaceutically acceptable acid addition salt thereof.
 4. Thecompound of claim 2 which is8-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dioneor a pharmaceutically acceptable acid addition salt thereof.
 5. Thecompound of claim 1 wherein R is the R₁,R₂ -glutarimide (b) or apharmaceutically acceptable acid addition salt thereof.
 6. The compoundof claim 5 which is1-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-4-methyl-4-propyl-2,6-piperidinedioneor a pharmaceutically acceptable acid addition salt thereof.
 7. Thecompound of claim 5 which is1-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-4,4-dimethyl-2,6-piperidinedioneor a pharmaceutically acceptable acid addition salt thereof.
 8. Thecompound of claim 5 which is1-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-4,4-diethyl-2,6-piperidinedioneor a pharmaceutically acceptable acid addition salt thereof.
 9. Thecompound of claim 2 which is8-[4-[4-(6-chloro-1,2-benzisoxazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dioneor a pharmaceutically acceptable salt thereof.
 10. The process forameliorating a psychotic state in a mammal in need of such treatmentwhich comprises systemic administration to said mammal an effective doseof from about 0.01 to 40 mg/kg body weight of a compound of claim
 1. 11.The process of claim 10 in which the compound is8-[4-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione.12.8-[4-[4-(2,1-Benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro[4.5]decane-7,9-dione.